SCHIEMANN Aromatic Fluorination

G. Balz, G. Schiemann, Aromatic fluorine compounds. I. A new method for their preparation, Chem. Ber. 60 (1927) 1186. 

Balz, G. Schiemann. G. Ber. Dtsch. Chem. Ges. 1927, 60, 1186. Gunther Schiemann was bom in Breslau, Germany in 1899. In 1925, he received his doctorate at Breslau, where he became an assistant professor. In 1950, he became the Chair of Technical Chemistry at Istanbul, where he extensively studied aromatic fluorine compounds. 

Aromatic fluorination involves analogous methods to those used in the aliphatic series. The most utilized methods are electrophihc fluorination (F2, N— F reagents) and nucleophilic fluorination through the Balz-Schiemann reaction (diazotation in the presence of fluoride ion). This latter method is of prime importance in industry. When the aromatic ring is activated by one or several electron-withdrawing groups, the... 

In most of cases, the fluorine atom(s) or the CF3 group(s) is borne by aromatic rings. Synthesis of these compounds for the optimization of hits as well as for parallel synthesis is done using the numerous fluoro aromatic or heterocyclic compounds that are commercially available. These latter compounds generally come from aromatic fluorination or trifluoromethylation reactions (especially the Balz-Schiemann reaction) and from heterocyclization reactions. However, fluoroaliphatic chains and fluorofunctionalities are more and more present, because of their pharmacological properties. Some examples are given in this section. 

Diazotization procedures. Widely used for the production of aromatic fluorine is the Balz-Schiemann reaction. The approach involves diazotization of the aniline and isolation of the insoluble tetrafluoroborate salt, followed by decomposition under heating conditions (Fig. 32). Initially introduced in 1927 [137,138], it did not achieve commercial utility until the mid-1980s. A modification of the Balz-Schie-mann reaction involves replacing the tetrafluoroborate with other counterions such as a fluorine anion [139],... 

Aromatic fluorination chemistry has a remarkably long history, and the first successful synthesis of aryl C-F bonds was reported in 1870 [22], Significant developments in the area in the early part of the 20th century included the discovery of Balz-Schiemann reaction [23,24] involving diazotization of an aromatic amine in the presence of tetrafluoroboric acid and the reaction scheme is shown in Fig. 4. The above reaction produces large quantities of waste (such as NaBF4,... 

A. Roe, Preparation of Aromatic Fluorine Compounds from Diazonium Fluoroborates The Schiemann Reaction, Org. React. 1949, 5, 193-228. 

Since dialkyltriazenes were first used in aromatic fluorination by Wallach, ° many fluoroaro-matic compounds have been obtained in high yield by the decomposition of 3,3-dialkyl-l-aryl-triazenes with various fluorides in acidic media (see Vol. ElOa, p 725fT). Aryltriazenes are a potential source of aryldiazonium salts under controlled, mild, acid conditions. Therefore, this replacement (Route A) can be considered as a type of Balz-Schiemann reaction (see Section... 

Aromatic fluorination by the silver ion-promoted decomposition of aryl-diazo sulfldes is similar to the Balz-Schiemann process. It provides efficient utilization of stoichiometric levels of fluoride ion, but has yet to be used for heterocyclic synthesis (91JOC4993). 

Whilst Sn2 displacement is a viable strategy for aliphatic fluorination, nucleophilic fluorination of aromatic systems is much more challenging. The traditional approach to aromatic fluorination is the Balz-Schiemann reaction, which is the thermal decomposition of aiyl diazonium tetra-fluoroborate salts, which are potentially explosive reagents. This decomposition also gives the toxic, fuming gas BF3 as a by-product and this should be removed in a basic aqueous scrubber. Modern alternatives should seek to provide safer and cleaner aromatic fluorination protocols. 

The Schiemann reaction seems to be the best method for the selective introduction of a fluorine substituent onto an aromatic ring. The reaction works with many aromatic amines, including condensed aromatic amines. It is however of limited synthetic importance, since the yield usually decreases with additional substituents present at the aromatic ring. 

For the introduction of fluorine into aromatic and heteroaromatic compounds the photolytic fluoro-de-diazoniation sometimes has advantages compared with the corresponding thermal dediazoniation (Balz-Schiemann reaction, see Sec. 10.4). For aromatic substrates the reaction was studied by Rutherford et al. (1961), Christie and Paulath (1965), Petterson et al. (1971), and Becker and Israel (1979). Hexafluorophos-phates sometimes give better yields than tetrafluoroborates (Rutherford et al., 1961). In analogy to Balz-Schiemann reactions in solution (Fukuhara et al., 1987), photolytic fluoro-de-diazoniations of benzene derivatives with electron-withdrawing substituents give lower yields. 

For this reason, industrial fluorinations of aromatics are performed by other routes, mostly via the Schiemann or Halex reaction [54, 55]. As these processes are multi-step syntheses, they suffer from low total selectivity and waste production and demand high technical expenditure, i.e. a need for several pieces of apparatus. 

The Balz-Schiemann and Wallach reactions The Balz-Schiemann reaction (the thermal decomposition of an aryl diazonium salt. Scheme 46) was for many years the only practical method for the introduction of a fluorine atom into an aromatic ring not bearing electron-withdrawing substituents. This reaction, first reported in the late 1800s, was studied in fluorine-18 chemistry as early as 1967 [214]. It involves the generation of an aryl cation by thermal decomposition, which then reacts with solvent, nucleophiles or other species present to produce a substituted aromatic compound. Use of fluorine-18-labelled... 

Diazotization in the presence of boron trifluoride enables diazonium tetrafluoroborates to be isolated from the reaction mixture and purified. Subsequent controlled decomposition produces the required fluoroaromatic. Although explosion hazards and the toxicity of the isolated salts are significant concerns with this process, known as the Balz-Schiemann process, 4,4 -di-fluorobenzophenone (BDF. 6) has been prepared by this route as a monomer for the production of the engineering plastic poly(ether ether ketone) , or PEEK , by condensation with 1,4-dihydroxybenzene in the presence of potassium carbonate. BDF 6 is superior to its chlorine analog because in aromatic systems the nucleophilic displacement of fluorine is more facile than that of chlorine, leading to a shorter polymerization time and a better quality product containing less degradation impurities. 

Due to the corrosive and toxic nature of volatile hydrogen fluoride, the fluorodediazoniation of aromatic and heteroaromatic amines in anhydrous hydrogen fluoride (see Section 26.1.2.), though very efficient, inexpensive and easy to scale up, needs special apparatus and safety measures which are not always available in every laboratory. Thus, the Balz-Schiemann reaction remains the most popular way to substitute aromatic amino groups for fluorine on a laboratory scale. Moreover, special techniques have been developed during the last decade to control formation, storage and decomposition of arenediazonium tetrafluoroborates on a large scale. 

Fig. 32. Balz-Schiemann synthesis of fluorinated aromatic rings.

Boron trifluoride forms addition compounds that incorporate an sp hybridized boron into a tetravalent structure. Salts of BF4 are readily formed with BF3 and a suitable fluoride donor. Halogen fluorides such as chlorine trifluoride react with BF3 to generate interhalogen cations such as [C1F2]+[BF4]. Some further examples are shown in equations (43) and (44). In an organic application, the Schiemann reaction provides an entry into fluorinated aromatics by thermal decomposition of a diazonimn tetrafluoroborate (equation 45). 

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